Fibrodysplasia ossificans progressiva (FOP) is a congenital and progressive disorder that cause a wide range of ossification of soft tissue and/or muscle after birth (Non-Patent Documents 1-3). Main symptoms of the disease are severe weakness, decreased life expectancy due to joint adhesion, and restrictive ventilatory impairment associated with the thoracic region. The respiratory function in FOP patients is gradually impaired, eventually causing death at about 40 years old due to respiratory failure. There is no effective treatment for preventing FOP-related ectopic ossification. The recent studies revealed that mutation of activin A receptor 1 (ACVR1) known as BMP type I receptor ALK2 causes the disease (Non-Patent Documents 3-9). One of the most common mutations of ALK2 is R206H which is considered to cause a change in kinase activity of ALK2, thereby inducing a constitutive increase in kinase activity of ALK2. For example, some other mutations of ALK2 such as G356D have been reported in the case of phenotypic variation of FOP. It is reported that such mutations also affect kinase activity so as to cause constitutive activation of ALK2 (Non-Patent Document 10). Therefore, it has been shown that kinase activity of ALK2 (G356D) is weaker than that of ALK2 (R206H), suggesting that such clinical change is derived from differences in bioactivity of ALK2 mutants (Non-Patent Document 11).
In addition, diseases caused by decreased functions of mitochondria are collectively referred to as “mitochondrial diseases.” Typical mitochondrial diseases are chronic progressive external ophthalmoplegia (CPEO), myoclonus epilepsy associated with ragged-red fibers (MERRF), and mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS). The mitochondrial diseases show a variety of morphological conditions because mitochondria do not uniformly cause abnormalities in all in vivo cells, and therefore, the diseases are intractable diseases for which there is no fundamental treatment.
Further; lysosomal diseases are caused by deletion of enzymes associated with lysosome which is an organelle. The diseases cause in vivo accumulation of substances that should be disintegrated under normal conditions. Lysosomal diseases have different names and symptoms depending on the types of deleted enzymes. At present, there exist about 30 types of lysosomal diseases. Currently available methods for treating lysosomal diseases include enzyme replacement therapy, organ transplantation, and bone-marrow transplantation. However, such methods provide substantially no effect on some symptoms. There is no known fundamental treatment.
Meanwhile, induced pluripotent stem cells (iPS cells) derived from somatic cells of patients are expected to be used as potential tools not only for biomedical studies but also for investigation of effects of drugs acting on cells derived from patients. It has been revealed that iPS cells generated from cells affected by a specific disease can reproduce phenotypes related to the disease. However, it is still unknown how disease-specific pathogenicity influences generation and maintenance of human iPS cells. There is no known example demonstrating that iPS cells can be produced for intractable diseases such as fibrodysplasia ossificans progressiva, mitochondrial diseases, and lysosomal diseases.